The dualistic mode of action of the vasodilator drug, nicorandil, differentiated by glibenclamide in 86Rb flux studies in rabbit isolated vascular smooth muscle

(1) In rabbit isolated aorta, the effects of the antianginal drug, nicorandil, of the K+ channel opener, cromakalim, and of the nitrovasodilator, sodium nitroprusside, on 86Rb efflux and on contractile force were compared. (2) In ion flux studies using 86Rb as a marker of K+ ions, both nicorandil and cromakalim, but not sodium nitroprusside, increased the efflux of 86Rb in non-stimulated preparations. The increase of membrane K+ conductance induced by nicorandil and cromakalim was totally suppressed by 10(-5) mol/l of the sulfonylurea derivative, glibenclamide. (3) The vasoconstrictor drug, noradrenaline (3 x 10(-7) mol/l), effectively increased the rate of 86Rb efflux. This stimulatory response was unaffected by glibenclamide, but was totally inhibited by Ca2+ depletion suggesting that the activation of Ca2(+)-sensitive K+ channels was responsible for this action of noradrenaline. (4) Sodium nitroprusside and nicorandil, the latter in the presence of glibenclamide to suppress the glibenclamide-sensitive stimulatory component on 86Rb efflux, antagonized the noradrenaline-induced increase in 86Rb efflux, while cromakalim in the presence of glibenclamide had no effect. (5) All of the vasodilators relaxed rabbit aortic strips contracted by 10(-7) mol/l noradrenaline in a concentration-dependent manner. (6) The vasodilatory response to cromakalim was antagonized by glibenclamide, whereas the relaxant action of nicorandil and of sodium nitroprusside remained unaffected. (7) These results demonstrate that under particular experimental circumstances, nicorandil can behave in vascular smooth muscle both as an opener of glibenclamide-sensitive K+ channels, and as a directly acting nitrovasodilator which acts via reduction of cellular calcium levels.